Pancreatic proliferative potential: protracted posting

Following up on yesterday‘s posting regarding the role of p16INK4a in ß-cell regeneration, here’s another article describing the decrease in islet cell proliferative potential with age. From Maedler et al.:

Type 2 diabetes is characterized by a deficit in ß-cell mass, and its incidence increases with age. Here, we analyzed ß-cell turnover in islets from 2- to 3- compared with 7- to 8-month-old rats and in human islets from 53 organ donors with ages ranging from 17 to 74 years. In cultured islets from 2- to 3-month-old rats, the age at which rats are usually investigated, increasing glucose from 5.5 to 11.1 mmol/l decreased ß-cell apoptosis, which was augmented when glucose was further increased to 33.3 mmol/l. In parallel, ß-cell proliferation was increased by both 11.1 and 33.3 mmol/l glucose compared with 5.5 mmol/l. In contrast, in islets from 7- to 8-month-old rats and from adult humans, increasing glucose concentrations from 5.5 to 33.3 mmol/l induced a linear increase in ß-cell death and a decrease in proliferation. … Therefore, differences in glucose sensitivity between human and 2- to 3-month-old rat islets may be due to both differences in age and in the genetic background. These data provide a possible explanation for the increased incidence of type 2 diabetes at an older age and support the use of islets from older rats as a more appropriate model to study glucose-induced ß-cell apoptosis.

The experimental paradigm is a bit different from the one used in yesterday’s featured article (Krishnamurthy et al.), which looked at recovery of ß-cells after destruction with a toxin. Here, the authors study the effects of glucose toxicity. (Per the proteotoxicity idea I described yesterday, I’m guessing that the basis of the toxicity is the secretory/protein folding burden placed on the cell by dramatically increased insulin production.)

In both papers, we see a decrease in ß-cell self-renewal capacity with age. Sitting looking at the two together, one obvious question is whether the decrease in glucose stress tolerance in old cells requires functional p16INK4a. Based on Krishnamurthy et al.‘s results, I’d predict that old ß cells in p16INK4a-/- animals respond to glucose in the same way as young cells, or at least show increased survival compared to cells from p16INK4a+/+ littermates under the same conditions. Smart money says those experiments are already underway.